Abstract
Transforming growth factor-β1 (TGF-β1)-induced myofibroblast transdifferentiation from orbital fibroblasts is known to dominate tissue remodeling and fibrosis in Graves’ ophthalmopathy (GO). However, the signaling pathways through which TGF-β1 activates Graves’ orbital fibroblasts remain unclear. This study investigated the role of the mitogen-activated protein kinase (MAPK) pathway in TGF-β1-induced myofibroblast transdifferentiation in human Graves’ orbital fibroblasts. The MAPK pathway was assessed by measuring the phosphorylation of p38, c-Jun N-terminal kinase (JNK), and extracellular-signal-regulated kinase (ERK) by Western blots. The expression of connective tissue growth factor (CTGF), α-smooth muscle actin (α-SMA), and fibronectin representing fibrogenesis was estimated. The activities of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) responsible for extracellular matrix (ECM) metabolism were analyzed. Specific pharmacologic kinase inhibitors were used to confirm the involvement of the MAPK pathway. After treatment with TGF-β1, the phosphorylation levels of p38 and JNK, but not ERK, were increased. CTGF, α-SMA, and fibronectin, as well as TIMP-1 and TIMP-3, were upregulated, whereas the activities of MMP-2/-9 were inhibited. The effects of TGF-β1 on the expression of these factors were eliminated by p38 and JNK inhibitors. The results suggested that TGF-β1 could induce myofibroblast transdifferentiation in human Graves’ orbital fibroblasts through the p38 and JNK pathways.
Highlights
Graves’ ophthalmopathy (GO) is an autoimmune disorder characterized by initial inflammation and later tissue expansion, remodeling, and/or fibrosis, causing cosmetically disfiguring and vision-threatening morbidities [1,2]
The results suggested that Transforming growth factor-β1 (TGF-β1) activated p38 and Jun N-terminal kinase (JNK) in the mitogen-activated protein kinase (MAPK) pathway in human Graves’ orbital fibroblasts
Evidence has shown that TGF-β1 induces Graves’ orbital fibroblasts to differentiate into myofibroblasts, which dominates the pathogenic processes of tissue remodeling and fibrosis [6,7]
Summary
Graves’ ophthalmopathy (GO) is an autoimmune disorder characterized by initial inflammation and later tissue expansion, remodeling, and/or fibrosis, causing cosmetically disfiguring and vision-threatening morbidities [1,2]. Transforming growth factor-β (TGF-β) is believed to induce tissue remodeling and fibrosis through myofibroblast transdifferentiation in Graves’ orbital fibroblasts [6,7]. Previous studies have confirmed the higher protein and messenger ribonucleic acid (mRNA) expression levels of TGF-β1 in Graves’ orbital tissues and orbital fibroblasts [8,9,10], the molecular mechanisms responsible for TGF-β1-induced myofibroblast transdifferentiation in GO have not been established. Matrix metalloproteinases (MMPs) belong to a family characterized by zinc-containing endopeptidases that are capable of degrading various ECM proteins, while tissue inhibitors of metalloproteinases (TIMPs) are specific endogenous inhibitors of MMPs. Several studies have reported that TGF-β1 regulates the expression of MMPs and TIMPs, resulting in ECM remodeling in several fibrotic disorders, including systemic sclerosis, idiopathic pulmonary fibrosis, and myelofibrosis [14,15,16]. The molecular pathways of which are still under investigation
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